Individual variability in alcohol sensitivity is among the most widely studied endophenotypes for alcohol dependence. However, little is known about brain mechanisms relevant for alcohol sensitivity. Research on human alcohol sensitivity phenotypes has often relied on self-report measures and conventional oral alcohol administration paradigms, both of which may introduce considerable measurement error, thus decreasing sensitivity for detecting genetic and neural correlates. The proposed study will examine neural markers of alcohol sensitivity in the context of an alcohol challenge paradigm that incorporates highly controlled intravenous ethanol infusion. The broad aims of this proposal include a) developing our approach for integrating fMRI and infusion;b) examining feasibility of studying neural correlates of alcohol sensitivity in this context;and c) estimating effect sizes to inform power analyses for future studies. Heavy-drinking young adults will participate in two infusion sessions: a baseline "acclimation" session and an fMRI session. Physiologically- Based Pharmacokinetic (PBPK) modeling will be used to establish a peak target blood alcohol concentration (BAC) of 0.06 1 0.005 g% within 15 minutes. This BAC will be maintained (clamped) for 90 minutes. Alcohol sensitivity indices will include traditional self-report measures;heart rate response during infusion;and serial measures of subjective intoxication (stimulation/sedation) across the session. We will examine these indicators in relation to BOLD responses during tasks that engage incentive motivation and cognitive control networks, incorporating repeated assessments across the BAC time course. Both traditional and brain-based measures of alcohol sensitivity will be examined in relation to self-reported drinking. By examining neural phenotypes in the context of acute alcohol exposure, we hope to identify brain-based alcohol sensitivity phenotypes that are potentially more sensitive to genetic variation and to behavioral outcomes as compared to traditional measures. ) PUBLIC HEALTH RELEVANCE: Physiological sensitivity to alcohol is demonstrated to predict future risk for alcohol dependence. However, little is known about brain mechanisms relevant for alcohol sensitivity. This research aims to examine brain-based measures of alcohol sensitivity that could be useful as biomarkers for the risk for alcohol dependence.